Long-term adjuvant ADT improves results of brachy boost therapy in unfavorable-risk prostate cancer patients

TROG 01.03 RADAR, begun in 2003, was a  (partly) randomized clinical trial to help optimize therapy of unfavorable-risk patients. It explored such topics as use of Zometa, radiation dose escalation, and optimal duration of androgen deprivation therapy (ADT) when given along with ("adjuvant" to) radiation therapy (RT).

• Zometa did not delay progression, which is similar to the STAMPEDE trial finding among men with metastatic hormone-sensitive prostate cancer when it was used without Celebrex. 
• The external-beam radiation (EBRT) doses they explored (66 Gy, 70 Gy and 74 Gy) were below today's standard of care (78 Gy-82 Gy), so have become irrelevant to current practice. 
• The assignment to various radiation doses was not randomized. 
• The benefit of long-term ADT (28 months vs 4 months) with dose-escalated EBRT in unfavorable-risk patients was proved by the DART 01/05 GICOR trial. 

Based on the Kishan et al. study, brachy boost therapy may be the preferred treatment option for high-risk patients So we will turn our focus to the only outstanding question that this major trial can still shed light on - what duration of adjuvant ADT is necessary when unfavorable-risk patients are treated with high dose rate brachy-boost therapy (HDRBBT)?

Joseph et al. reported the 10-year outcomes of the TROG 01.03 RADAR trial conducted at 24 sites in Australia and New Zealand. From 2003 to 2007, patients were randomized on 6 vs 18 months of adjuvant ADT . There were 1,051 evaluable unfavorable-risk patients defined as:

• Stage T2b-4 or
• Stage T2a and Gleason score≥7 and PSA≥10 ng/ml
• NCCN risk groups: 31% unfavorable intermediate-risk, 66% high-risk
• Patients with positive pelvic lymph nodes (stage N1) or distant metastases (stage M1) on a bone scan/CT were excluded

The HDRBBT treatment given to 237 patients consisted of:

• 46 Gy in 23 treatments of EBRT followed by 19.5 Gy in 3 HDR brachy treatments (biologically equivalent to 88 Gy if given as EBRT-only)
• All patients received 6 months of adjuvant ADT (Lupron) starting 5 months before EBRT 
• Half were randomized to get 12 extra months of ADT (total =18 months) 
• Pelvic lymph nodes were not treated

Distant progression (radiographic progression on a bone scan/CT) was the primary endpoint. The 10-year outcomes for those receiving HDRBBT were:

• 20% distant progression (25% less than 74 Gy EBRT)
• 2% local progression (71% less than 74 Gy EBRT)
• 15% bone progression (31% less than 74 Gy EBRT)
• 9% prostate cancer-specific mortality (25% less than 74 Gy EBRT)
• 23% all cause mortality (31% less than 74 Gy EBRT)
• Distant progression was reduced by 39% by the longer ADT treatment. It was statistically significant even after adjustment for potentially confounding risk factors.
• Longer ADT was beneficial independent of RT dose, whether EBRT or HDRBBT
• 13% of men receiving HDRBBT suffered urethral strictures vs 4% of men receiving 74 Gy EBRT (for full toxicity data, see this report)
• The cumulative incidence of transition to castration resistance was significantly lower in men receiving 18 months of adjuvant ADT with RT (in an earlier report)

This establishes the importance of adding long-term (18 months) ADT for all unfavorable risk patients receiving radiation as a primary treatment. The adjuvant ADT gave better outcomes independent of the radiation dose. The Nabid et al trial proved that 18 months is as useful as 36 months in high-risk patients. But rather than slavish adherence to a single number, NCCN recommends 18 months to 3 years of adjuvant, at the discretion of the doctor.

The patient may wish to get more if:

• there are multiple high-risk features (e.g., GS9-10, PSA>20, T3/4, PNI, rare histology, genomic risk)
• there is suspicion of lymph node metastases, especially from advanced PET scans
• side effects are very tolerable

The patient may wish to get less if:

• there are lower risk features (e.g., GS 6-8, PSA<10, T2, no genomic risk)
• advanced PET scans (Axumin or PSMA) are negative
• side effects are onerous
• treatment is entirely extremely hypofractionated (HDR brachy or SBRT monotherapy)
• an additional systemic treatment (e.g., docetaxel, Zytiga, Xtandi, Erleada, or Nubiqa) is used experimentally

In an earlier observational meta-analysis (see this link), adjuvant ADT did not seem to add benefit to brachy boost therapy. This once again shows the limitation of observational studies. Only randomized clinical trials can provide the definitive proof we desire for decision-making.

Some patients think they can delay the transition to castration-resistance by eliminating or reducing the amount of ADT used with their RT. This shows that does not happen. Castration resistance is a consequence of genomic breakdown that always occurs as the cancer evolves. It may be facilitated by eliminating the hormone-sensitive cells and leaving only castration-resistant cells (this is called "competitive release"). By eliminating cancer cells as early as possible (before metastases have been detected) using HDRBBT and long-term adjuvant ADT, there is an opportunity to cure the disease. We are learning that cancer cells signal other cancer cells via extracellular vesicles to become like them. Even if it does not cure the patient, the profound reduction of the cancer load has a bigger effect on castration resistance than drug resistance does. This phenomenon was also noted in the TOAD randomized clinical trial (see this link). After there are metastases, an "evolutionary" personalized strategy (like this one) may be preferable.